The traditional method of administering therapeutic agents to treat diseases of the internal organs and vasculature has been by systemic delivery. Systemic delivery involves administering a therapeutic agent at a discrete location followed by the agent migrating throughout the patient's body including, of course, to the afflicted organ or area of the vasculature. But to achieve a therapeutic amount of the agent at the afflicted site, an initial dose substantially greater than the therapeutic amount must be administered to account for the dilution the agent undergoes as it travels through the body. Systemic delivery introduces the therapeutic agent in two ways: into the digestive tract (enteral administration) or into the vascular system (parenteral administration), either directly, such as injection into a vein or an artery, or indirectly, such as injection into a muscle or into the bone marrow. Absorption, distribution, metabolism, excretion and toxicity, the ADMET factors, strongly influence delivery by each of these routes. For enteric administration, factors such as a compound's solubility, its stability in the acidic environs of the stomach and its ability to permeate the intestinal wall all affect drug absorption and therefore its bioavailability. For parenteral delivery, factors such as enzymatic degradation, lipophilic/hydrophilic partitioning coefficient, lifetime in circulation, protein binding, etc. will affect the agent's bioavailability.
At the other end of the spectrum is local delivery, which comprises administering the therapeutic agent directly to the afflicted site. With localized delivery, the ADMET factors tend to be less important than with systemic administration because administration is essentially directly to the treatment site. Thus, the initial dose can be at or very close to the therapeutic amount. With time, some of the locally delivered therapeutic agent may diffuse over a wider region, but that is not the intent of localized delivery, and the diffused portion's concentration will ordinarily be sub-therapeutic, i.e., too low to have a therapeutic effect. Nevertheless, localized delivery of therapeutic agents is currently considered a state-of-the-art approach to the treatment of many diseases such as cancer and atherosclerosis.
Localized delivery of therapeutic agents may be accomplished using implantable medical devices. Coating implantable medical devices with therapeutic agents, however, is not without problems.
The family of mussel adhesive proteins is unique in that they bond to a large variety of substrates in an aqueous environment. These proteins share numerous molecular motifs, however, approximately 25% of amino acids in a particular mussel adhesive protein is the modified amino acid 3,4-dihydroxyphenyl-L-alanine (DOPA). It has further been determined that mussel adhesion to rocks, wood and metal is due in large part to DOPA. It has been found, however, that the portion of DOPA responsible for the remarkable adhesive capability of these polymers is the 3,4-dihydroxyphenyl group. The present invention takes advantage of the strong binding properties of 3,4-dihydroxyphenyl, and 2,3-dihydroxyphenyl, to provide novel biodegradable coatings, primarily for use as primer coatings for implantable medical devices, particularly bare metal implantable medical devices.